The recent progress in molecular medicine has led to certain improvements in diagnostics and treatment of neoplastic diseases. In spite of this partial success, these pathologies remain a considerable challenge. For certain types of cancers, the current therapy in some cases fails for a number of reasons. On the one hand, it is inherent resistance of tumour cells, their ability of constant mutation and therapy evasion, on the other hand it is also the heterogeneity of the tumour environment (Hanahan D, Weinberg R A. Hallmarks of cancer: the next generation. Cell 2011; 144:646-674). It was shown that tumours of the same type highly differ for individual subjects from the viewpoint of their genomic profile (Jones S et al. Core signalling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321:1801-1806. Parsons D W et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008; 321.1807-1812.), which indicates the necessity of the so-called “personal” therapy. Even a bigger problem is the heterogeneity of mutations in the same tumour, as it has been recently shown for renal tumours (Gerlinger M et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366:883-892.), and this situation can be expected for other types of tumours as well. For this reason it is necessary to search for new approaches and for an invariable intervention point(s) common for all or most malignant cells in the tumour and which preferably affects essential functions in cancer cells. It seems that such an intervention point could be mitochondria, i.e. organelles which are fundamental for the generation of energy necessary for all physiological as well as pathophysiological processes in cells. Although tumour cells use, from a major part, the so-called aerobic glycolysis for energy generation, mitochondrial respiration (i.e. consumption of oxygen linked to ATP formation) is inherent to most (if not all) types of tumours (Ralph S J et al. The causes of cancer revisited: “mitochondrial malignancy” and ROS-induced oncogenic transformation—why mitochondria are targets for cancer therapy. Mol Aspects Med 2010; 31:145-170.).
A group of substances with anti-cancer activity was defined under the name “mitocans” (derived from “mitochondria and cancer”) (Neuzil J et al. Molecular mechanism of ‘mitocan’-induced apoptosis in cancer cells epitomizes the multiple roles of reactive oxygen species and Bcl-2 family proteins. FEBS Lett 2008; 580:5125-5129. Neuzil J et al. Classification of mitocans, anti-cancer drugs acting on mitochondria. Mitochondrion 2013; 13:199-208.). These substances are divided into several groups according to the molecular mechanism of their activity. These are: (1) hexokinase inhibitors; (2) agents targeting Bcl-2 family proteins; (3) redox-active agents acting as thiol inhibitors; (4) agents targeting the VDAC and ANT proteins; (5) agents targeted the electron redox chain; (6) lipophilic targeting the internal mitochondrial membrane; (7) agents targeting the Krebs cycle; (8) agents targeting the mitochondrial DNA; (9) agents that belong to none of these groups. Examples of these agents and their targets are shown in FIG. 1.
Breast cancer is a neoplastic disease which is very difficult to treat and which is currently diagnosed at one in eight women during their life-span. Treatment of breast cancer commonly based on tamoxifen (TAX) therapy. Approximately 30% of breast cancer patients are diagnosed with high level of the HER2 protein, which belongs to the group of receptor tyrosine kinases and which increases the proliferative capacity of cells, enhancing their malignant potential (Arteaga C L et al. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol. 2011; 9:16-32.). The established therapy (where the main drug used is TAX) is ineffective because tumours featuring high HER2 levels are rather resistant to this therapy. TAX affects oestrogen receptors in the plasma membrane of breast cancer cells, whereby it inhibits important processes linked to the for proliferation capacity of cancer cells. It has been published recently that at higher concentrations, TAX acts not only via the oestrogen receptor, but it also moves to the inner mitochondrial membrane, where it interacts with complex I of the respiratory chain (Moreira P I et al. Tamoxifen and estradiol interact with the flavin mononucleotide site of complex I leading to mitochondrial failure. J Biol Chem 2006; 281:10143-10152.). This occurs, however, at doses which are not easy to achieve from a pharmacological point of view. Moreover, it is possible to expect an increased toxicity of TAX in case of such high doses.
At present, breast cancer with high HER2 protein is treated with the humanised antibody “trastuzumab”, which inhibits HER2 activity. This therapy is economically highly demanding and features a secondary toxicity; furthermore a large percentage of subjects with high HER2 protein are resistant to trastuzumab (it is estimated to be about 30%). Rather challenging is also the recently introduced drug lapatinib that inhibits receptor tyrosine kinases (Ewer M S, Ewer S M. Cardiotoxicity of anticancer treatments: what the cardiologist needs to know. Nat Rev Cardiol 2010; 7:564575. Lin S X et al. Molecular therapy of breast cancer: progress and future directions. Nat Rev Endocrinol 2010; 6:485-493. Ahn E R et al. is the improved efficacy of trastuzumab and lapatinib combination worth the added toxicity? Breast Cancer 2012; 6:191-207.). An issue in this context is that lapatinib is not a specific HER2 inhibitor, which may lead to the inhibition of other receptor tyrosine kinases, too, and to secondary toxicity, and it is also possible to anticipate development of resistance to this therapy (Wetterskog D et al. Identification of novel determinants of resistance to lapatinib in ERBB2-amplified cancers. Oncogene 2013; 1-11).